71IN - Anti CTLA4 and Predictive Biomarkers

Abstract

ABSTRACT The recent US FDA and EU EMA regulatory approval of ipilimumab, a CTLA-4 antibody, has highlighted the need for pharmacodynamic and predictive markers of its clinical benefit. Ipilimumab's RECIST response rate is in the realm of 10%, with another 10-20% of patients having clinical benefit with stable disease past 6 months. Response and overall survival are related pharmacokinetically to its Cminns levels, although the rate of immune related adverse events also rises with increased dose. Several studies in the metastatic and adjuvant settings have defined pharmacodynamics and predictive markers for ipilimumab and determine if they are associated with clinical benefit. HLA-DR, as well as the activation marker ICOS are increased on CD4 and CD8 T cells after ipilimumab treatment. An increase in the early total lymphocyte count may be associated with outcome. Microarray analyses suggest that expression of a large number of genes are altered in CD4 T cells by ipilimumab, but fewer genes are impacted in CD8 T cells. Central memory cells are increased, with a corresponding decrease in naive T cells. Gata3, a Th2 polarizing molecule was increased, yet TH17 cell induction and IL-17 levels were increased. Examination of tumors in patients treated with ipilimumab revealed a significant influx of CD8 T cells, which may be primarily PD-1 positive. In an adjuvant trial, pre-treatment CD8/EOMES/Ki67 positive T cells were significantly associated with relapse-free survival, and CD4/EOMES/Ki67 T cells were associated with low levels of irAEs, the mechanism-based side effects of ipilimumab. Analysis of tumor gene expression by microarrays suggest that an immune signature may also be predictive of benefit. The newly developed checkpoint inhibitor antibodies against PD-1 have been associated with excellent responses of long duration in melanoma, renal cell cancer and non-small cell lung cancer. Increases in circulating T regulatory cells and CD4/CTLA-4 expressing T cells was associated with response in one study. In tumors, PD-1 expression assessed by immunohistochemical staining was associated with outcome, and no patient with absent PD-L1 expression responded. These data provide a rationale for further marker testing and novel trials of sequenced antibodies. Disclosure J.S. Weber: I have received honraria of less than 10,000 USD from BMS, have sat on advisory boards for BMS, and my institution has received research money from BMS